JP2573521B2 - P-tert-butoxyphenylalkyl alcohol and method for producing the same - Google Patents

Description

The present invention is useful as a precursor for obtaining a known p-hydroxyphenylalkyl alcohol used as an intermediate for pharmaceuticals, agricultural chemicals, liquid crystal polymers and the like. New p-
The present invention relates to tert-butoxyphenylalkyl alcohol and a method for producing the same.

2. Description of the Related Art Known pn-butoxyphenylpropanol, which is an isomer of the compound of the present invention, is obtained by hydrogenating pn-butoxycinnamic acid ester to form pn-butoxyphenylpropionate, which is then converted to lithium aluminum hydride. Obtained by reduction with

However, the de-n-butylation reaction of pn-butoxyphenylpropanol requires a treatment under severe conditions as shown in the comparative production examples described below, and involves side reactions, so that the desired p-hydroxyphenylpropanol cannot be obtained. You can't get it.

On the other hand, a benzyl group, a methoxymethyl group, a 2-hydropyranyl group, a dimethyl-tert-butylsilyl group, and the like are generally used for protecting a phenolic hydroxyl group.

However, these protecting groups provide operability, safety,
It has disadvantages in economy and the like.

SUMMARY OF THE INVENTION The present invention provides a p-tert-butoxyphenylalkyl alcohol useful as a precursor for obtaining a p-hydroxyphenylalkyl alcohol in place of the above-mentioned conventional compound, and a method for producing the same. .

Therefore, there is a demand for a novel precursor for obtaining p-hydroxyphenylalkyl alcohol instead of the conventional compound, and for the creation of a technique for synthesizing it on an industrial scale with a high yield.

B) Configuration of the Invention Means for Solving the Problems The present inventors have intensively studied to solve the above-described problems of the conventional technology. As a result, the novel p-type of the present invention having a tert-butyl group as a protecting group for a phenolic hydroxyl group.
It has been found that by using tert-butoxyphenylalkyl alcohol, p-hydroxyphenylalkyl alcohol can be obtained at lower cost and in higher yield than using pn-butoxypropanol. That is, as shown in Reference Production Examples 1 to 3 below, the thus obtained p-tert-butoxyphenylalkyl alcohol is treated with a de-tert-butylating agent such as hydrochloric acid or sulfuric acid, or
By adding a non-volatile acid such as toluenesulfonic acid and distilling off isobutylene produced under reduced pressure to the outside of the reaction system, it was found that p-hydroxyphenylalkyl alcohol was quickly led to p-hydroxyphenylalkyl alcohol. It has been found to be useful as a precursor for obtaining alcohol.

That is, the first gist of the present invention is that the general formula And a p-tert-butoxyphenylalkyl alcohol represented by the formula:

The second aspect of the present invention is based on the general formula In the p-tert-butoxyphenylmagnesium halide represented by the general formula X '(CH ₂ ) _n OM (II) (wherein X and X' are the same or different halogen atoms, M is an alkali metal, halogenated Wherein n represents an integer of 3 to 5), and a compound represented by the formula: is reacted in the presence of a copper halide catalyst. And a process for producing p-tert-butoxyphenylalkyl alcohol represented by the formula:

Next, the synthesis route of p-tert-butoxyphenylalkyl alcohol of the compound of formula (I) of the present invention is as shown below.

Next, the method for synthesizing the compound of the formula (I) of the present invention will be described in detail.

First, the compound of the formula (III) of the Grignard reagent, which is a raw material for synthesizing the compound of the formula (I) of the present invention, is a known compound and may be obtained by a known method or a commercially available product.

X in the compound of the formula (III) is a halogen atom, chlorine,
Iodine, bromine and the like.

In the compound of the formula (II), examples of M are alkali metals, such as sodium, lithium and potassium, and examples of alkaline earth metal halides include magnesium chloride. And can be used. For example, as a specific example of the compound of the formula (II), sodium 5-bromopentyloxy obtained by reacting sodium hydride with 5-bromo-1-pentanol is obtained by reacting n-butyllithium with 4-chloro-butanol. 4-Chlorobutoxylithium obtained by reacting 4-chlorobutoxylithium with methylmagnesium chloride, which is a Grignard reagent of methylchloride, and 3-chloro-1-propanol are exemplified.

As described above, the Grignard reagent which reacts with ω-haloalkylhydrin [M of the compound of formula (III) is a hydrogen atom] such as 3-chloro-1-propanol can use the compound of formula (III) as it is, but is expensive. Therefore, it is more advantageous to use inexpensive methyl (or ethyl) magnesium halide. Useful methyl (or ethyl) magnesium halides include chloride, bromide, iodide and the like.

The halogen atom of the copper halide catalyst used includes chlorine, bromine, iodine and the like. Useful copper halide catalysts include cuprous chloride, cuprous bromide, cuprous iodide, lithium chloride and cupric chloride complexes, and the like.

Next, a Grignard reagent of the compound of formula (III) is reacted with the compound of formula (II) in the presence of a copper halide catalyst,
The operation of the cross-coupling reaction to obtain the desired compound of formula (I) is shown below.

First, 10 g of a Grignard reagent solution of the compound of formula (III) is added.
^-4 to 10 ^-1 molar amount, preferably 10 ^-3 to 10 ^-2 molar amount of a copper halide catalyst is added, and at a temperature of 40 to 120 ° C, the compound of the formula (II)
The solution of the compound is added dropwise, and stirring is continued for 1 to 5 hours to obtain the desired compound of formula (I).

Examples of the solvent used in the cross coupling reaction include ethers such as tetrahydrofuran, diethyl ether and dibutyl ether.

In the cross-coupling reaction, the reactivity decreases as the alkyl chain of the compound of formula (II) becomes longer.
It is desirable to use bromide or iodide for the compound (I) or the compound of the formula (II), and the reaction temperature must be 40 to 120 ° C.

After completion of the reaction, the mixture is hydrolyzed with an aqueous ammonium chloride solution or the like, and the organic layer is separated. The organic layer is washed with water, the solvent is distilled off, and the residue is distilled under reduced pressure to obtain the desired p-tert-butoxyphenylalkyl alcohol represented by the formula (I).

The methods for synthesizing the compound of formula (I) described above are shown in Examples 1 to 3.

Example 1 Production of p-tert-butoxyphenylpropanol A stirrer and a reflux condenser were attached, and the atmosphere was replaced with nitrogen.
Butoxyphenyl magnesium chloride (1.5 mol /
) Was added, followed by 1.0 g (0.01 mol) of cuprous chloride. And 82.3 g of methyl magnesium chloride in advance
(1.1 mol) and 94.5 g of 3-chloro-1-propanol
(1.0 mol) was reacted with 153.3 g (1 mol) of 3-chloropropoxy magnesium chloride at 50-70 ° C.
The mixture was added dropwise over a period of time, and stirring was continued at the same temperature for 2 hours. Next, the reaction solution is poured into 500 ml of a saturated aqueous solution of ammonium chloride, and 500 ml of toluene is further added thereto to separate the organic layer. The organic layer is washed with water and then dehydrated with anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was distilled under reduced pressure to obtain p-tert-butoxyphenylpropanol as a fraction having a boiling point of 140 ° C./2 mmHg189.
6g (gas chromatography purity 99.8%, yield 91.0%)
I got

The analytical values of p-tert-butoxyphenylpropanol thus obtained were as follows.

(1) Elemental analysis value C (%) H (%) calculated value 75.0 9.7 Actual measured value 75.2 9.8 (2) NMR spectrum δ 1.30 (9H, s, H ^a ) δ 2.60 (2H, t, H ^d ) δ 1.70 (1H, s, H ^g ) δ 1.88 (2H, guint, H ^e ) δ 3.56 (2H, t, H ^f ) δ 6.76 (2H, d, H ^b ) δ 6.96 (2H, d, H ^c ) (3) Infrared absorption spectrum 3350 cm ^-1 OH stretching Example 2 Method for producing p-tert-butoxyphenylbutanol Same as Example 1 Then, 667 ml (1.0 mol) of a tetrahydrofuran solution of p-tert-butoxyphenylmagnesium chloride (1.5 mol /) was added to a 4-diameter flask, followed by 1.4 g (0.01 mol) of cuprous chloride. Then, a solution of 64.1 g (1.0 mol) of n-butyllithium in diethyl ether and 108.6 g (1.0 mol) of 4-chloro-1-butanol were added thereto.
Mole)) to give 4-chlorobutoxylithium 11
4.5 g (1.0 mol) was added dropwise at 90-100 ° C over 2 hours, and stirring was continued at the same temperature for 2 hours. Next, the reaction solution was poured into 500 ml of a saturated aqueous solution of ammonium chloride, and 500 ml of toluene was further added to separate an organic layer. And
After washing with water, it was dehydrated with anhydrous sodium sulfate. Then, the solvent is distilled off,
Distillation was performed under reduced pressure to obtain a p-t fraction as a fraction having a boiling point of 140 ° C./2 mmHg.
189.6 g of ert-butoxyphenylbutanol (gas chromatography purity 99.8%, yield 85.3%) was obtained.

The analytical values of p-tert-butoxyphenylbutanol thus obtained were as follows.

(1) Elemental analysis value C (%) H (%) calculated value 75.6 10.0 Actual value 75.9 10.1 (2) NMR spectrum δ 1.39 (9H, s, H ^a ) δ 2.63 (2H, t, H ^d ) δ 1.90 (1H, s, H ^h ) δ 1.62 (4H, m, H ^ef ) δ 3.68 (2H, t, H ^g ) [delta] 6.83 Similarly ^{(2H, d, H b)} δ 7.09 and ^{(2H, d, H c)} (3) preparation example 1 of the infrared absorption spectrum 3360cm ^-1 OH stretching example 3 p-tert-butoxy phenyl pentanol 667 ml (1.0 mol) of a tetrahydrofuran solution of p-tert-butoxyphenylmagnesium chloride (1.5 mol /) was placed in a 4-diameter flask, followed by lithium copper (II) tetrachloride (tetrahydrofuran solution, 0.1 mol / l).
01 mol). Then, 189.0 g (1.0 mol) of sodium 5-bromopentyloxy obtained by previously reacting 24.0 g (1.0 mol) of sodium hydride with 167.0 g (1.0 mol) of 5-bromo-1-pentanol was added to 80- The mixture was added dropwise at 100 ° C. over 2 hours, and stirring was continued at the same temperature for 2 hours. Next, the reaction solution was poured into 500 ml of a saturated aqueous solution of ammonium chloride, and 500 ml of toluene was further added to separate an organic layer. And after washing with water, it was dehydrated with anhydrous sodium sulfate.
Then, the solvent is distilled off and distilled under reduced pressure to give a boiling point of 162 ° C /
As a fraction of 1 mmHg, 189.6 g of p-tert-butoxyphenylpentanol (purity of gas chromatography: 99.8%, yield: 80.2%) was obtained.

The analytical values of p-tert-butoxyphenylpentanol thus obtained were as follows.

(1) Elemental analysis value C (%) H (%) calculated value 76.2 10.2 Actual measured value 76.3 10.4 (2) NMR spectrum δ 1.30 (9H, s, H ^a ) δ 2.53 (2H, t, H ^d ) δ 1.35 to 1.80 (7H, m, H ^efgi ) δ 3.56 (2H, t, H ^h ) δ 6.76 (2H, d, H ^{b) δ 6.98 (2H, d} , H c) (3) p-tert- flask 300ml capacity equipped with a infrared absorption spectrum 3355cm ^-1 OH stretching reference example 1 p-hydroxyphenyl-propanol of preparation stirrer 104.2 g (0.5 mol) of butoxyphenylpropanol was added, and 150 g of concentrated hydrochloric acid was added dropwise at 25 to 30 ° C., and stirring was continued for 2 hours.

After the reaction, neutralize with 270 ml of 10% aqueous sodium carbonate
Extracted with ml of dichloromethane. Thereafter, the solvent was distilled off to obtain crude crystals of p-hydroxyphenylpropanol. Then, 70.1 g (gas chromatography purity 99.9%, yield 9) as a fraction having a boiling point of 167 ° C./2 mmHg was obtained by vacuum distillation.
2.1%).

The analysis values of p-hydroxyphenylpropanol thus obtained were as shown below, and the NMR spectrum and infrared absorption spectrum were completely consistent with the standard.

(1) Melting point 51-54 ° C (2) NMR spectrum δ 1.74 (2H, guint, H e) δ 6.69 (2H, d, H b) δ 2.57 (2H, tri, H d) δ 7.08 (2H, d, H c) δ 3.29 (1H, s, H g) δ 8.08 (1H, s, H a) δ 3.54 (2H, tri, H f) (3) 300ml marked with a infrared absorption spectrum 3352cm ^-1 OH stretching reference production example 2 p-hydroxyphenyl-butanol preparation stirrer 111.2 g (0.5 mol) of p-tert-butoxyphenylbutanol in a capacity of 4
100 g of 0% sulfuric acid was added dropwise and stirring was continued for 2 hours.

After the reaction, neutralize with 270 ml of 10% aqueous sodium carbonate
Extracted with ml of dichloromethane. Thereafter, the solvent was distilled off to obtain crude crystals of p-hydroxyphenylbutanol.
300 ml of hexane was added thereto, the mixture was stirred for 30 minutes, and the crystals obtained by filtration were dried to obtain 75.0 g of white crystals (gas chromatography purity: 99.7%, yield: 90.3%).

The analytical values of p-hydroxyphenylbutanol thus obtained are as follows, and the NMR spectrum,
The infrared absorption spectrum was completely consistent with the sample.

(1) Melting point 52-55 ° C (2) NMR spectrum δ 1.29~1.80 (4H, m, H ef) δ 6.74 (2H, d,
H ^b ) δ 2.51 (2H, tri, H ^d ) δ 7.03 (2H, d,
^{H c) δ 3.14 (1H,} s, H h) δ 8.10 (1H, s,
^{H a) δ 3.54 (2H,} tri, to H ^g) (3) Infrared absorption spectrum 3351cm ^-1 OH stretching Reference Example 3 p- hydroxy flask 300ml capacity equipped with a preparation stirrer phenylpentanols p- tert-butoxyphenylpentanol 118.2 g (0.5 mol), p-
Put 5 g of toluenesulfonic acid and use an aspirator,
The mixture was kept at 40 ° C. for 2 hours while stirring with a magnetic stirrer under reduced pressure (25 mmHg) to distill off the generated isobutylene gas.

After the reaction, neutralize with 270 ml of 10% aqueous sodium carbonate
Extracted with ml of dichloromethane. Thereafter, the solvent was distilled off to obtain crude crystals of p-hydroxyphenylpentanol. 300 ml of hexane was added thereto, and the mixture was stirred for 30 minutes. The crystals obtained by filtration were dried to obtain 80.8 g of white crystals (purity of gas chromatography: 99.6%, yield: 89.8%).

The analytical values of p-hydroxyphenylpentanol thus obtained were as shown below, and the NMR spectrum and infrared absorption spectrum were completely consistent with the standard.

(1) Melting point 65-66 ° C (2) NMR spectrum δ 1.37 to 1.81 (7H, m, ^Hefgi ) δ 6.73 (2H, d, H
^b ) δ 2.51 (2H, t, H ^d ) δ 7.01 (2H, d,
^{H c) δ 3.55 (2H,} t, H h) δ 8.04 (1H, s,
H ^a ) (3) Infrared absorption spectrum 3351 cm ^-1 OH stretching Comparative Production Example 20.8 g (0.1 mol) of pn-butoxyphenylpropanol and 30 g (0.3 mol) of concentrated hydrochloric acid were placed in a 100 ml flask and heated at 25 to 30 ° C. Stirring was continued for 2 hours, but no change was observed. Stirring was continued at reflux temperature for 5 hours, but there was no change. Similarly, 30 g of concentrated hydrobromic acid was added in place of the above concentrated hydrochloric acid, and stirring was continued for 5 hours at the reflux temperature. As a result, the raw material had disappeared, but the desired p-hydroxyphenylpropanol was not obtained. As by-products, pn-butoxyphenylpropyl bromide in which the alcohol moiety was brominated and p-hydroxyphenylpropyl bromide in part were formed.

C) Effect of the Invention The p-tert-butoxyphenylalkyl alcohol of the present invention is treated with a butylating agent, or a non-volatile acid is added and isobutylene produced under reduced pressure is distilled out of the reaction system to obtain a medicament. , P-hydroxyphenylalkyl alcohol, which is important as a synthetic intermediate such as agrochemicals and liquid crystal polymers, can be easily obtained at low cost and in high yield.

Claims (2)

(57) [Claims] (1) General formula (In the formula, n represents an integer of 3 to 5.) p-tert-butoxyphenylalkyl alcohol represented by the following formula: 2. The general formula (Wherein X represents a halogen atom). X- (CH ₂ ) _n OM ( _where X ′ is a halogen atom, M is an alkali metal, halogen) Wherein n represents an integer of 3 to 5), and a compound represented by the following formula is reacted in the presence of a copper halide catalyst. (In the formula, n represents an integer of 3 to 5.) A method for producing p-tert-butoxyphenylalkyl alcohol represented by the following formula: